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Thursday, April 23, 2015

Absolute HBsAg Levels, Not Percent Decline May Be Goal of HBV RNAi

I just walked into an early morning session at the International
Liver Congress in Vienna and may have learned the most important nugget of
information regarding RNAi treatment for HBV.

During the discussion in the ‘Banishing B’ session, Dr.
Joerg Petersen referred to clinical analyses to be presented this Saturday
showing that patients who achieve HBsAg levels of less than 500, or even better 200 IU/ml and then
are given an interferon have a much better chance of eventually losing HBsAg,
i.e. being functionally cured, than those that do not.

Dr. Petersen has been involved in clinical studies combining
nukes and an interferon, and data presented at last year’s American Liver
meeting (AASLD) showed that 9% treated with the combination for 1 year lost HBsAg in the
year following combination therapy compared to just 2.8% receiving interferon
alone.

Note that currently only interferons are thought to give you
a chance of functionally curing HBV by medication and that HBsAg seroconversion
attributed to interferon treatment may occur in the years after cessation of
interferon therapy. It will therefore be
important to see whether this increase in seroconversion with combination
treatment continues to hold up in subsequent years. The nukes are ‘only’
thought to protect the liver from the ongoing damage from HBV replication and may
have to be given indefinitely.

I am not sure whether the new insight comes from a fresh
clinical study or are the result of a more detailed subgroup analysis of the
previous study. Regardless, it hammers
home a message that can be heard again and again, even more so in Vienna this year than
at the London meeting last year: it is all
about HBsAg lowering.

Implications for HBV
RNAi

The implications of the new analysis for RNAi approaches for
the treatment of HBV is obvious: use RNAi to get HBsAg below the
threshold. In other words, it may be less
about getting a magical 1log knockdown, but more about getting patients below 500IU/ml.

For this, Dr. Petersen recommended using 2 nukes so that the
tiny and very slow HBsAg declines observed on nukes continue ( < 0.1 log per year). With
RNAi agents, you would likely achieve this goal for a patient with an HBsAg at
baseline of 1000IU/ml within a month, even with a single 2mg/kg dose of ARC520
from Arrowhead Research as reported last year.

The absolute knockdown potency of an RNAi agent would
determine which fraction of the HBV population fall within this sweet spot.
With a 1log knockdown e.g. you could start RNAi with patients with as much as
5000IU/ml.

For the clinical development of RNAi agents for HBV, the
first step will be to determine the HBsAg decline on a background of
nukes (just what Arrowhead is doing right now). For pivotal trials, an
immunostimulatory agent such as an interferon should be added to the nukeà RNAi/nuke treatment
regimen to finish off the virus.

Stay tuned to learn about the fold benefit of HBV cures in
patients falling below the 500IU/ml threshold, and the 3-4mg/kg single-dose
results for ARC520 from Arrowhead Research to be reported later this quarter (note to Arrowhead PR department: next Monday may be a good time to do so).

REPLICor...single agent they claim most/all rebound after treatment. In combination, they say all s-seroconvert. There is A LOT of skepticism around REPLICor. One questioner challenged them why they have not published the results 2 years after presenting similar data from the Bangladesh trial at AASLD. Reply was vague and indicated that there were doubts about mechanism of action (e.g. potential innate immune stimulation). So nothing really changed for me, except to see that also in the hepatology community (not only in the oligoRx community) there is this skepticism.

RGLS...it is now about whether RG-101 can enable 4-week pangenotypic treatments. That's always been the base case.

I own both ARWR & TKMR. Both companies have acknowledged that to achieve functional cure will require combinational therapy to knock down antigen along with other aspect of infection. I guess it's just matter of who can reach this goal first? Timing wise, isn't ARWR ahead of both TKMR & Replicor?

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